Lack of galectin-1 exacerbates hepatocarcinogenesis in a chronically inflamed liver

Introduction. Chronic liver inflammation (CLI) is a risk factor for development of hepatocellular carcinoma (HCC). Galectin-1 (Gal1) is involved in the regulation of inflammation, angiogenesis and tumorigenesis, exhibiting multiple anti-inflammatory and pro-tumorigenic activities. We aimed to explore its regulatory role in CLI and HCC progression using an established model of CLI-mediated HCC development, Mdr2(Abcb4)-knockout mice, which express high levels of Gal1 in the liver.

Materials and methods. We generated double-knockout Gal1-KO/Mdr2-KO (dKO) mice on C57BL/6 and FVB/N genetic backgrounds and compared HCC development in the generated strains with their parental Mdr2-KO strains. Transcript expression was tested by RT-PCR and nanostring assay. Protein expression was tested by immunoblotting and immunohistochemistry.

Results and discussion. Loss of Gal1 increased liver injury, inflammation, fibrosis, and ductular reaction in dKO mice starting from early age. Aged dKO mutants displayed earlier hepatocarcinogenesis and increased tumor size compared to control Mdr2-KO mice. This was also accompanied by higher hepatic tumor penetrance, worsened tumor differentiation and higher tumor cell pleomorphism in dKO mutants. Osteopontin, a well-known modulator of HCC development, was over-expressed in dKO livers at all tested animal ages.

Conclusions. Our results demonstrate that, in Mdr2-KO mice, a model of CLI-mediated HCC, Gal1 mediated protection from hepatitis, liver fibrosis and HCC initiation, dominates over its known pro-carcinogenic activities at later stages of HCC development. Collectively, these findings suggest that anti-Gal1 treatments may not be applicable at all stages of CLI-mediated HCC.